The present invention relates to a controlled release dosage form containing quetiapine or its salt especially quetiapine fumarate.
Quetiapine, 2-[2-(4-dibenzo[b,f] [1,4] thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol of the formula (I):
is an antipsychotic agent indicated for treatment of various types of psychoses.
The quetiapine compound as well as the fumarate salt thereof have been disclosed, e.g., in EP 240228. The patent application WO 2004/078735 disclosed various crystalline polymorphs of quetiapine fumarate, particularly crystalline polymorph Form I, Form II, and an amorphous product.
As a pharmaceutical drug, quetiapine is marketed as quetiapine fumarate (technically a hemifumarate salt, i.e., a 2:1 molar ratio of base to acid ion). It is a white crystalline powder (m.p. 172-173° C.) that is moderately soluble in water. It is sold under the brand name SEROQUEL® (AstraZeneca), e.g. within a pharmaceutical tablet comprising from 25 to 400 mg of the quetiapine fumarate, calculated as the free base. Inactive ingredients are listed (see, for instance, Rote Liste 2003) as povidone, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, magnesium stearate, hydroxypropylmethyl cellulose, Macrogol 400, titanium dioxide. The tablets are coated with (coloured) lacquer. The composition provides for immediate release of quetiapine after oral administration, i.e. the whole bolus is released in the stomach environment.
Quetiapine fumarate is a powder compound with relatively very low density, so that it is very prone for segregation within tabletting processes and direct tabletting is very difficult, if not impossible when high percentages of quetiapine are in the blend.
Furthermore, the therapeutical dose of quetiapine is relatively high. This leads to a need of making compositions with relatively high concentrations of the active (up to 60%). Making tablets of such a high concentration of quetiapine fumarate is difficult, particularly due to the bad tabletting properties of the active.
An advantageous alternative to the immediate release formulation of quetiapine fumarate is a controlled release formulation, preferably exhibiting slow and/or constant release of the drug substance for several hours. Such a formulation can lower the total therapeutical dose that is necessary and/or reduce side effects, can allow for better bioavailability of the drug, and can avoid the need of repeated administration of the drug during a day.
EP 907,364 provides for a sustained release formulation comprising quetiapine and a gelling agent, preferably hydroxypropylmethylcellulose.
WO 2005-041935 provides for a sustained release formulation comprising quetiapine and a wax material.
Although sustained release compositions with quetiapine fumarate are suggested in the art, an alternative sustained or controlled release dosage form would be advantageous.